Abstract
The anxiolytic activity and tolerance of two dosage schedules of prazepam, a long plasma half-life benzodiazepine, were compared under double-blind conditions in two groups of 10 inpatients each who met Research Diagnostic Criteria for Generalized Anxiety Disorder and presented chronic and severe symptomatology. Patients received prazepam 40 mg per day on one of two dosage schedules: 1) divided dosage (DD) - 10 mg in the morning and at noon and 20 mg in the evening; or 2) single dosage (SD) - 40 mg in the evening. The 3 weeks of therapy were preceded and followed by 1 week of wash-out for baseline and follow-up assessments, which were performed weekly with the Hamilton Anxiety Scale, Clinical Global Impression, rating of morning drowsiness and evening worsening of symptoms, and patient self-rating of anxiety by means of a visual analogue scale performed both in the morning and in the afternoon. The results showed a clear superiority of the DD over the SD schedule: better anxiolytic efficacy on the Hamilton Anxiety Scale (P<0.0005) and on both morning and afternoon visual analogue scales (P<0.01 andP<0.0002); less morning drowsiness (P<0.0001); and steadier anxiolytic effect during the daytime, as globally rated by the investigator (P<0.0001) or measured by morning-afternoon differences on the visual analogue scale (P<0.005). These results suggest that plasma pharmacokinetics alone may not be sufficient to predict the duration of benzodiazepine anxiolytic activity.
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References
Achte K (1980) Use of benzodiazepines in psychiatric inpatients. Arzneimittelforsch 30:902–905
Amrein R, Leishman B (1980) Importance of pharmacokinetic data for clinical practice. In: Priest RG, Filho UV, Amrein R, Skreta M (eds) Benzodiazepines today and tomorrow. Lancaster, England, MTP Press, pp 61–75
Anhalt HS, Young R, Roginsky M (1980) Double-blind comparison of ketazolam, diazepam and placebo in once-a-day vs TID dosing. J Clin Psychiatry 41:386–392
Ansseau M, Doumont A, Diricq St (1984) Methodology required to show clinical differences between benzodiazepines. Curr Med Res Opin [Suppl 4] 8:108–114
Ayd FJ Jr (1984) Benzodiazepine withdrawal phenomena: New insights. Psychiatr Ann 14:133–134
Barbizet J (1979) Etude comparative prazepam — diazepam en milieu psychiatrioue. Psychologie Médicale (Paris) 11:1525–1532
Balter MB, Manheimer DI, Mellinger GD, Uhlenhuth EH (1984) A cross-national comparison of anti-anxiety/sedative drug use. Curr Med Res Opin [Suppl 4] 8:5–20
Bellantuono C, Reggi V, Tognoni G, Garattini S (1980) Benzodiazepines: Clinical pharmacology and therapeutic use. Drugs 19:195–219
Bergamo ML, Sudol TE (1982) Value of once daily dosing of diazepam questioned- and defended. J Clin Psychopharmacol 2:355–356
Blackwell B (1976) Treatment adherence. Br J Psychiatry 129:513–531
Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218
Bowden CL (1978) Double-blind placebo-controlled trial of ketazolam in anxiety. Curr Ther Res 24:170–178
Breimer DD, Jochemsen R, von Albert HH (1980) Pharmacokinetics of benzodiazepines: Short-acting versus long-acting. Arzneimittelforsch 30:875–881
Burrows DG, Dumovic P, Smith JA, Norman T, Maguire K (1977) A controlled comparative trial of clorazepate (Tranxene) and diazepam (Valium) for anxiety. Med J Aust 2:525–528
Committee on the Review of Medicines (1980) Systematic review of the benzodiazepines: Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Br Med J 280:910–912
Detti I (1983) Benzodiazepines in the treatment of insomnia: Pharmacokinetic considerations. In: Costa E (ed) The benzodiazepines: From molecular biology to clinical practice. New York, Raven Press, pp 173–199
Dunlop E, Weisberg J (1968) Double-blind study of prazepam in the treatment of anxiety. Psychosomatics 9:75–78
Dureman I, Malmgren H, Norrman B (1978) Comparison studies of clorazepate administered as a divided daily dose and as a single dose at night. Psychopharmacology 57:123–126
Fabre LF Jr, McLendon DM (1979) Ketazolam administered once-a-day compared to clorazepate TID and placebo in a double-blind study to anxious outpatients. Curr Ther Res 25:710–720
Fabre LF Jr, Harris RT, Stubbs DF (1976) Double-blind placebo-controlled efficacy study of ketazolam (U-28,774). J Int Med Res 4:50–54
Fabre LF Jr, McLendon DM, Gainey A (1978) Double-blind comparison of ketazolam administered once-a-day with diazepam and placebo in anxious outpatients. Curr Ther Res 24:875–882
Fabre LF Jr, McLendon DM, Mallette A (1980) Phase IV out-patient comparison study of prazepam against placebo, diazepam, and chlorazepate dipotassium in anxiety. Curr Ther Res 28:784–791
Feighner JP (1980) Ketazolam once-a-day in the treatment of anxiety: A double-blind comparison with diazepam and placebo. Curr Ther Res 28:425–431
Fontaine R, Annable, L, Chouinard G, Ogilvie RI (1983) Bromazepam and diazepam in generalized anxiety: A placebo-controlled study with measurement of drug plasma concentrations. J Clin Psychopharmacol 3:80–87
Gallant DM, Guerrero-Figueroa R, Swanson WC (1973) U-28,774 (ketazolam): An early evaluation of new antianxiety agent. Curr Ther Res 15:123–126
Goldberg HL, Finnerty RJ (1977) A double-blind study of prazepam versus placebo in single daily doses in the treatment of anxiety. Compr Psychiatry 18:147–155
Greenblatt DJ (1980) Benzodiazepines 1980: Current update (discussion). Psychosomatics [Suppl] 21:26
Greenblatt DJ, Shader RI (1978a) Pharmacotherapy of anxiety with benzodiazepines and β-adrenergic blockers. In: Lipton MA, DiMascio A, and Killam KF (eds) Psychopharmacology: A generation of progress, New York, Raven Press, pp 1381–1390
Greenblatt DJ, Shader RI (1978b) Prazepam and lorazepam, two new benzodiazepines. N Engl J Med 299:1342–1344
Greenblatt DJ, Shader RI, Abernethy DR (1983) Current status of benzodiazepines. N Engl J Med 309:410–416
Guy W (1976) ECDEU Assessment Manual for Psychopharmacology. 3rd ed., Rockville, National Institute of Mental Health
Haefely W, Möhler H (1980) Mechanism of action of the benzodiazepines. Roche Research Report
Hoffman-La Roche (1983) Data on file
Hamilton M (1959) The assessment of anxiety states by ratings. Br J Med Psychol 32:50–55
Kaplan SA, Jack ML (1983) Metabolism of the benzodiazepines: Pharmacokinetic and pharmacodynamic considerations. In: Costa E (ed) The Benzodiazepines: From molecular biology to clinical practice. New York, Raven Press, pp 173–199
Kaplan SA, Jack ML, Alexander K, Weinfeld RE (1973) Pharmacokinetic profile of diazepam in man following single intravenous and oral and chronic oral administrations. J Pharm Sci 62:1789–1796
Kim KK, Sirman A, Trainor FS, Lee BY (1980) Anxiolytic efficacy and safety of ketazolam compared with diazepam and placebo. Clin Ther Res 8:159–163
Kingstone E, Villeneuve A, Kossatz I (1966) Prazepam in the treatment of anxiety and tension: A clinical study of a new benzodiazepine derivative. Cur Ther Res 8:159–163
Kingstone E, Villeneuve A, Kossafz I (1969) Double-blind evaluation of prazepam, chlordiazepoxide and placebo in non-psychotics with anxiety and tension: Some methodological considerations. Curr Ther Res 11:106–114
Kleber RJ (1980) Ketazolam compared to diazepam and placebo in the treatment of anxiety. J Int Med Res 8:439–445
Kurowski M, Ott H, Herrmann WM (1982) Relationship between EEG dynamics and pharmacokinetics of the benzodiazepine lormetazepam. Pharmacopsychiatria 15:77–83
Lader M (1983) Benzodiazepine withdrawal states. In: Trimble MR (ed) Benzodiazepines divided. Chichester, John Wiley and Sons, pp 17–32
Magnus RV (1973) Once-a-day potassium clorazepate in anxiety. Br J Clin Pract 27:449–452
Magnus RV, Dean BC, Curry SH (1977) Clorazepate: Double-blind crossover comparison of a single nightly dose with diazepam thrice daily in anxiety. Dis Nerv Syst 38:819–821
Mellinger GD, Balter MB, Uhlenhuth EH (1984) Prevalence and correlates of the long term regular use of anxiolytics. JAMA 251:375–379
Miller RD, Strickland R, Davidson J, Parrot R (1983) Characteristics of schizophrenics and depressed patients excluded from clinical research. Am J Psychiatry 140:1205–1207
Möhler H, Richards JG (1983) Benzodiazepines receptors in the central nervous system. In: Costa E (ed) The benzodiazepines: From molecular biology to clinical practice. New York, Raven Press, pp 93–116
Owieczka J, Van Meerbeeck Ph, Nystrom C, Lens F (1981) Double-blind comparison of ketazolam and placebo administered once-a-day in the treatment of anxiety. Acta Ther 7:159–174
Petursson H, Lader RH (1981) Withdrawal from long-term benzodiazepine treatment. Br Med J 283:643–645
Post C, Lindgren S, Bertler A, Malmgren H (1977) Pharmaco-kinetics of N-desmethyldiazepam in healthy volunteers after single daily doses of dipotassium clorazepate. Psychopharmacology 53:105–109
Rickels K (1980) Benzodiazepines 1980: Current update (discussion). Psychosomatics [Suppl] 21:26
Rickels K, Sablosky L, Silverman H, Case WG, Rial W, Mirman M, Gottlieb S (1977) Prazepam in anxiety: A controlled clinical trial. Comp Psychiatry 18:239–249
Rickels K, Case WG, Csanalosi I, Weise CC, Goldstein ME, Greisman P (1980) Ketazolam, diazepam and placebo in anxious outpatients: A controlled study. J Clin Pharmacol 20:581
Rickels K, Case G, Downing RW, Winokur A (1983) Long-term diazepam therapy and clinical outcome. JAMA 250:767–771
Shader RI, Greenblatt DJ (1980) Benzodiazepines: Some aspects of their clinical pharmacology. In: Ciba Foundation Symposium 74: Drug concentrations in neuropsychiatry, Amsterdam, Excerpta Medica, pp 141–155
Shaffer JW, Yeganeh ML, Foxwell NH, Kurland AA (1968) A comparison of the effects of prazepam, chlordiazepoxide and placebo in the short-term treatment of convalescing alcoholics. J Clin Pharmacol 6:392–399
Smith MT, Evans LEJ, Eadie MJ, Tyrer JH (1979) Pharmaco-kinetics of prazepam in man. Eur J Clin Pharmacol 16:773–782
Solomon K, Hart R (1978) Pitfalls and prospects in clinical research on antianxiety drugs: Benzodiazepines and placebo —A research review. J Clin Psychiatry 39:823–831
Spitzer R, Endicott J, Robins E (1978) Research diagnostic criteria: Rationale and reliability. Arch Gen Psychiatry 34:773–782
Sugerman AA, Miksztal MW, Freymuth HW (1971) Comparison of prazepam and placebo in the treatment of convalescing narcotic addicts. J Clin Pharmacol 11:383–387
Tyrer P, Rutherford D, Huggett T (1981) Benzodiazepine withdrawal symptoms and propanolol. Lancet 1:520–522
Tyrer P, Owen R, Dawling S (1983) Gradual withdrawal of diazepam after long-term therapy. Lancet 1:1402–1406
Warnecke G (1977) Demetrin versus Placebo: Über die Wirkung von Prazepam bei psychosomatischen und vegetativ funktionellen Beschwerdebildern in der gynäkologischen Sprechstunde. Therapiewoche 27:8407–8417
Weir JH (1978) Prazepam in the treatment of anxiety: A placebo-controlled multicenter evaluation. J Clin Psychiatry 39:841–847
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Ansseau, M., Doumont, A., von Frenckell, R. et al. Duration of benzodiazepine clinical activity: Lack of direct relationship with plasma half-life. Psychopharmacology 84, 293–298 (1984). https://doi.org/10.1007/BF00555201
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DOI: https://doi.org/10.1007/BF00555201